(1) Field of the Invention
The present invention relates to novel topical compositions and method for the treatment of fungal nail disease. In particular, the present invention relates to the use of GRAS natural plant derivatives for this purpose.
(2) Description of Related Art
Fungal nail disease (onychomycosis) is the most commonly occurring nail disorder encountered in primary care. Current estimates indicate that nearly 11 million Americans are affected by fungal nail disease. It can affect toenails, fingernails or both and is usually caused by infectious organisms known as dermatophytes.
Fungal nail disease causes discoloration and thickening of the nail, accumulation of debris under the nail and, in severe cases, detachment of the nail plate from the nail bed. Toenails are the primary site of infection. Fungal nail disease can affect people of any age, gender and race and may cause discomfort and embarrassment due to the appearance of the nails.
Onychomycosis (Tine unguium) is defined as a localized infection of the nail or nail bed primarily caused by a pathogenic fungi; however, yeasts and molds can also cause infection. This disease is not life threatening, however, it can cause inconvenience, pain and discomfort to the individual and serve as a reservoir for infection. Infection can usually be determined by thickened, yellow or brown discolored, friable nail plates (Zaias, N., et al., J. Fam. Pract. 42 513-518 (1996)).
Onychomycosis affects up to 30% of the population by age 60. The most common dermatophytes are Trichophyton rubrum and Trichophyton mentagrophytes (Zaias, N., et al., J. Fam. Pract. 42 513-518 (1996)). Although there are numerous topical agents on the market, none have been found to be satisfactory (Zaias and Serrano, Clinical Experimental Dermatology 14(2) 120-123 (1989)). Consequently, emphasis in research studies has focused on oral treatments.
Fungal infection of the fingernails or toenails are caused most commonly by dermatophytes (Tricophyton rubrum, T. Mentagrophytes, Microsporum canis, Epidermophyton Floccosum and E. stockdale) which represent about 90% of the infection. Yeasts (Candida albicans, C. parapsilosis. and C. krusei) and nondermatophyte molds (Scytalidium hyalinum, S. dimidiatum, Fusarium oxysporum, F. moniliforme, Acremonium chrysogenum, A. strictum, Aspergillus terreus, A. flavus, and Scopulariopsis brevicaulis) are responsible for 7% and 3% of infections, respectively. These organisms infect the stratum corneum of the skin, hair and nails (Zaias, N., et al., J. Fam. Pract. 42 513-518 (1996); and Tom, C. M., et al., Am. J. Health-Syst. Pharm. 56 865-871 (1999)).
Immunodeficient patients, such as those with AIDS, the nail infection can be severe. Also, diabetics are known to be predisposed to certain cutaneous diseases but their frequency of infection is still not clear (Tom, C. M., et al., Am. J. Health-syst. Pharm. 56 865-871 (1999); and Lugo-Somalinos, A., et al., J. Am. Acad. Dermatol. 26 408-410 (1992)). There are four types of onychomycosis: (1) distal subungual onychomycosis (DSO) affecting the nail bed, (2) white superficial onychomycosis (WSO) affecting the surface of the nail plate, (3) proximal subungual onychomycosis (PSO) affecting the ventral and proximal area of the nail plate from the proximal nail fold, and (4) chronic mucocutaneous candidiasis (CMC) affecting the entire thickness of the nail plate (Zaias, N., et al., J. Fam. Pract. 42 513-518 (1996)).
DSO is the most common form and accounts for about 90% of the cases of onychomycosis. It is typically a lifelong infection and difficult to treat and is caused mainly by T. rubrum. A traumatized nail can become infected by species of Scytalidium or Scopulariopsis. WSO mainly involves the toenails and manifests itself as small, well-defined white spots on the surface of the nail plate. It is caused mainly by T. Mentagrophytes. PSO accounts for less than 1% of the cases and is rare in healthy adults but occurs frequently in patients with AIDS. This type is caused by a preexisting T. rubrum that predates immunosuppression. CMC accounts for less than 1% of onychomycosis cases and invasion of the nail is by C. albicans. Most commonly, the organism originates in the intestinal tract and spreads from the mouth to the hand, eventually affecting the nail plate, nail bed and nail fold (Zaias, N., et al., J. Fam. Pract. 42 513-518 (1996); and Tom, C. M., et al., Am. J. Health-Syst. Pharm. 56 865-871 (1999)).
Onychomycosis never resolves spontaneously and recurrence after treatment is common. Treatment is difficult because of the unique properties of the nail unit. Thus, an effective antifungal agent must enter the affected tissue and persist there in high concentrations. The existing therapies must be continuous and used until the infected nail grows out and even after this lengthy treatment low cure rates and quick relapse times are common (Zaias, N., et al., J. Fam. Pract. 42 513-518 (1996); and Tom, C. M., et al., Am. J. Health-syst. Pharm. 56 865-871 (1999)). Treatments with topical creams are not as effective as oral treatments and prolonged periods of application are required. Griseofulvin, terbinafine and itraconazole are the drugs usually used for oral treatment.
Orally administered drugs that are available on the market also suffer from various drawbacks. Some are not very effective in controlling the fungal infection, some produce unwanted side effects, and all are quite expensive when compared to topical drugs. For example, Einarson, Aridian and Shear (Einarson, et al., British Journal of Dermatology, 130 (Supplement 43), 32-34 (1994)) studied the cost-effectiveness of griseofulvin (GRI), ketoconazole (KET) and terbinafine (TER). The expected treatment costs for toenail onychomycosis were $1049.77 for TER, $1388.54 for GRI and $1936.48 for KET. At the same time, success rates of the treatments were 78.3% for TER, 40.8% for KET and 17.5% for GRI.
A study by Korting, Schafer, Korting, Zienicke, Georgii and Ollert (Korting H., et al., Antimicrobial-Agents-Chemotherapy 37 (10) 2064-2068 (1993)) concurs that griseofulvin is minimally successful. In addition to unremarkable success rates and high costs, Zaias and Drachman (Zaias, N., et al., Journal of the American Academy of Dermatology 9(6), 912-919 (1983)) also report serious side effects with ketoconazole. Both griseofulvin and ketoconazole can cause elevated liver enzymes and ketoconazole has been shown to cause anti-androgenic dysfunction in males and adrenal dysfunction (Zaias and Serrano, Clinical Experimental Dermatology 14(2), 120-123 (1989)).
Recently itraconazole has been introduced as an effective oral treatment for onychomycosis. Its clinical cure rates are between 72% and 80% (Doncker, Decrois, Pierard, Roeland, Woestenborghs, Jacomin, Odds, Heremans, Dockx and Roseeuw, Archives of Dermatology 132(1), 34-41 (1996)). However, the cost of itraconazole is high and side effects include elevations of serum transaminases, alkaline phosphatase and bilirubin. Additionally, there are numerous drug interactions, including phenytoin, rifampin, Carbamazepine, isoniazid, cyclosporin, digoxin, terfenadine and warfarin (Nurses Drug Guide, 1996). Despite these known problems, many health care practitioners are currently prescribing pulse therapy with itraconazole, consisting of monthly one-week cycles of 400 mg daily for three to four months (Doncker, Van-Lint, Dockx and Roseeuw, Cutis 56(3), 180-183 (1995)).
In sum, because of the high cost and potentially dangerous side effects of oral antifungal agents, there are still no solutions for the treatment of onychomycosis using non-prescription products. Onychomycosis remains a concern for a large number of individuals. In light of these circumstances, an alternative topical agent that is inexpensive, and effective is needed.
It is therefore an object of the present invention to provide topical compositions and a method for the use for treating fungal nail disease which produce very significant improvement. Further, it is an object of the present invention to provide compositions which use plant materials from natural sources which are GRAS General Recognized As Safe under U.S. regulations. Further still, it is an object of the present invention to provide compositions which are inexpensive. These and other objects will become increasingly apparent by reference to the following description and the drawings.
The present invention relates to a method for inhibiting a dermatophyte in an infected nail in humans which comprises:
multiple separate applications of an effective amount of a composition which consists of an active ingredient selected from the group consisting of camphor, menthol, eucalyptus oil, thy mol and mixtures thereof as active ingredients in a topical carrier to the nail until the dermatophyte is inhibited.
Further the present invention relates to a composition for treating a nail infection caused by a dermatophyte which consists essentially of:
(a) an effective amount of an active ingredient selected from the group consisting of camphor, menthol, eucalyptus oil, thymol and mixtures thereof; and
(b) a topical carrier, wherein the active ingredient is present in an amount between about 0.01 and 25% by weight of the composition.
Further still, the present invention relates to a kit for the treatment of a nail infection caused by a dermatophyte which comprises:
(a) a closed openable container containing a composition which consists essentially of an effective amount of an active ingredient selected from the group consisting of camphor, menthol, eucalyptus oil, thymol and mixtures thereof in a topical carrier; and
(b) application means for applying the composition on and under the nail which is infected with the dermatophyte.
The compositions can contain between 0.01 and 25% by weight of each of the ingredients based upon the weight of the composition. In a mixture of the four (4) ingredients the amount would be 100%. Preferably the amount is between about 1 and 10% by weight of each of the ingredients based upon the weight of the composition.